Project Abstract Bipolar Disorder is a major psychiatric disorder characterized by alternation between the extreme mood states of mania and depression. Many efficacious treatments exist; however, there is a high degree of variability in individual response. This frequently results in a lengthy trial and error process of treatment optimization which may take years. Lithium was the first mood stabilizing medication and is still the gold standard for treatment. Existing data suggests that lithium responsive bipolar disorder may be a distinct form of illness. There is a subset of patients who have a remarkably good response to lithium. These patients tend to have a family history of bipolar disorder and present with euphoric rather than irritable mania. Lithium response has also been shown to be familial. The goal of this project has been the identification of genes associated with response to lithium in bipolar disorder. In the last funding period, we studied a series of candidate genes in our retrospectively assessed sample of 184 patients. These studies found evidence for two genes predicting response to lithium. NTRK2 codes for the trkb receptor which is the receptor for BDNF also implicated in bipolar disorder. We found SNPs in the NTRK2 gene that were associated with response to lithium in those with euphoric mania but not associated in those with irritable mania. Conversely, the gene for the phosphodiesterase PDE11A was associated with response for all forms of mania. These data support the idea that lithium responsive bipolar disorder is genetically distinct. Retrospective data has numerous limitations. For this reason, we have also conducted a prospective clinical trial of lithium in bipolar disorder. Patients with bipolar disorder are first stabilized on lithium monotherapy over a three month period and then entered into the maintenance phase of the study. Patients are then followed for 2 years in order to detect relapse into mania or depression. SNPs are tested for association to response measured as time to relapse using a survival curve analysis. 75 subjects have entered the protocol to date. In this renewal, we propose to: 1) expand the retrospective sample to 500 subjects; 2) genotype the retrospective sample at an additional 50 genes; 3) recruit an additional 125 subjects into the prospective sample for a total of 200 and 4) replicate the most significant SNPs from the retrospective sample in the prospective sample. PUBLIC HEALTH RELEVANCE: Project Narrative: Bipolar disorder is a common psychiatric disorder characterized by alternation between the extreme mood states of mania and depression. Though it affects 1 - 3% of veterans overall, the rate may be several fold higher for combat exposed veterans returning from Iraq. Several good treatments exist, but there is a high variability in response to different medications in that treatment is often a lengthy trial and error process. The goal of this study is to identify genetic variation that is associated with a good therapeutic response to lithium in bipolar disorder. The results of this study could be used to develop a DNA based predictor of response to different medications. This could aid clinicians in the selection of medications and lead to faster stabilization and reduced suffering of veterans.